Triple metachronous primary brain tumors: sequential occurrence of astrocytoma, atypical meningioma, and high-grade glioma without radiotherapy exposure. Illustrative case

Abstract

BACKGROUND

Collision tumors, characterized by the coexistence of distinct histological tumor types in adjacent regions, are rare in neuro-oncology. While meningioma-glioma collisions are documented, sequential occurrence without a history of radiotherapy is exceptionally uncommon, posing diagnostic challenges and implying elusive pathogenic mechanisms.

OBSERVATIONS

A 31-year-old female underwent resection of a left frontal WHO grade I–II astrocytoma (2000) without radiotherapy. Eighteen years later, she developed an atypical meningioma (WHO grade II) at the same site, confirmed histologically and immunohistochemically (epithelial membrane antigen positive/glial fibrillary acidic protein negative). Seven years thereafter, a high-grade glioma (WHO grade 3) with oligodendroglioma-like features and a 1p/19q co-deletion emerged. Molecular profiling revealed divergent alterations: the meningioma exhibited NCOR2/CHD4/ELP1 mutations and 22q deletion, while the glioma harbored IDH2 p.R172H, TERT promoter, NOTCH1, and CIC mutations, supporting metachronous primary tumors despite shared 1p/19q loss.

LESSONS

This case underscores that metachronous collision tumors can arise without radiotherapy, necessitating histopathological and molecular integration for accurate diagnosis. Long-term vigilance is critical for detecting sequential tumors, and shared microenvironments or genetic pathways may underlie tumorigenesis. Comprehensive profiling aids in clarifying pathogenesis and guiding management.

https://thejns.org/doi/10.3171/CASE26149

Meningiomas and gliomas represent the most prevalent primary brain tumors, with meningiomas accounting for approximately 24%–30% of intracranial neoplasms and gliomas comprising 20.3%.¹ While these tumors typically arise independently, rare cases exhibit the coexistence of distinct histological tumor types in adjacent or overlapping regions, a phenomenon termed collision tumors in neuro-oncology.² The simultaneous occurrence of different tumor types in the nervous system is exceptionally uncommon and is primarily linked to prior radiation exposure or tumor engulfment mechanisms. However, sporadic reports describe such cases without any history of radiotherapy or chemotherapy, suggesting alternative, poorly understood pathogenic mechanisms.³ Current research indicates that collision tumors involving gliomas and meningiomas may share overlapping genetic alterations, including mutations in CDKN2A, TAF1L, CSMD3, and PDGF, which could contribute to their development.^4,5 Despite these findings, the precise molecular mechanisms driving the formation of collision tumors remain elusive. Some hypotheses suggest microenvironmental interactions, “field cancerization” or shared progenitor cell origins, although further investigation is required.^5–7 Given the rarity of these cases, expanding the pool of reported collision tumor cases, particularly those without prior radiation exposure, is crucial for uncovering underlying biological pathways.

In this report, we present a unique case of a patient who sequentially developed three primary brain tumors: initially a low-grade astrocytoma (WHO grade I–II), followed by an atypical meningioma (WHO grade II), and finally a high-grade glioma (WHO grade 3) in the same or adjacent anatomical region, without receiving prior radiation therapy or chemotherapy. This case highlights the diagnostic and therapeutic challenges posed by collision tumors and underscores the need for comprehensive molecular profiling to better understand their pathogenesis.

Illustrative Case

Initial Presentation and Management of Low-Grade Astrocytoma

A 31-year-old woman presented in 2000 with persistent headaches. Neurological examination was nonfocal. Neuroimaging studies (technique unspecified per original records) demonstrated a left frontal lobe mass exhibiting space-occupying effects. She underwent left frontal craniotomy with documented gross-total resection of the lesion. Histopathological assessment confirmed a diffusely infiltrating astrocytoma, classified as WHO grade I–II, based on standard morphological criteria of the era. Postoperatively, she received brief adjuvant chemotherapy (regimen unspecified in archival documents) without radiotherapy. Recovery was uneventfully with no early recurrence.

Diagnosis of Radiation-Naïve Atypical Meningioma (18 years after first surgery)

Eighteen years after the initial surgery, the patient presented with progressive apathy, executive dysfunction, and recurrent focal seizures over 2 months. Given the history of left frontal astrocytoma, MRI findings were initially interpreted as definitive glioma recurrence: a left frontal heterogeneously enhancing mass (6.3 × 4.5 cm) with cystic components, irregular ring enhancement, significant perilesional edema, and midline shift (Fig. 1A). Preoperative multidisciplinary consensus strongly favored transformed high-grade glioma. Histopathological analysis revealed an atypical meningioma (WHO grade II). The tumor exhibited classical meningothelial whorls with nuclear atypia and spontaneous necrosis (Fig. 1B). Immunohistochemical (IHC) analysis further bolstered this unexpected diagnosis: diffuse strong vimentin (VIM) and membranous epithelial membrane antigen (EMA) expression, accompanied by CD34 positivity outlining the rich tumor vasculature, but a complete absence of glial markers (glial fibrillary acidic protein [GFAP]/S100 negative). Coupled with a Ki-67 index of 10%, these findings were irreconcilable with a glial lineage (Fig. 1C–H).

FIG. 1.

Neuroimaging and histopathological findings of the atypical meningioma at the second surgical intervention. A: T1-weighted contrast-enhanced axial (left), coronal (center), and sagittal (right) MR images revealing a heterogeneously enhancing mass (6.3 × 4.5 cm) in the left frontal lobe with cystic components, irregular ring enhancement, and significant perilesional edema causing midline shift. B: Hematoxylin and eosin (H&E) staining at low power (original magnification ×4) demonstrating characteristic meningothelial whorls; the upper right inset shows high-power details of marked nuclear atypia, and the lower right inset highlights areas of spontaneous necrosis. C–H: IHC staining (original magnification ×20) showing diffuse membranous expression of EMA (C), strong cytoplasmic positivity for VIM (D), CD34 highlighting the intratumoral vascular network (E), complete absence of GFAP expression (F), negativity for S100 protein (G), and a Ki-67 proliferation index of approximately 10% (H).

Recurrence of High-Grade Glioma With Oligodendroglioma-Like Features (7 years after second surgery)

Twenty-five years after the initial presentation (and 7 years after the second resection), surveillance MRI showed recurrence: a left frontal lesion (5.5 × 4.8 cm) with restricted diffusion (diffusion-weighte imaging hyperintensity and apparent diffusion coefficient hypointensity), inhomogeneous contrast enhancement, and two suspicious enhancing nodules in the left ventricular trigone (Fig. 2A). Given the patient’s previous diagnostic history, a broad differential diagnosis was maintained. Despite divergent radiological opinions (primary radiation-naïve WHO grade I–II astrocytoma to spontaneous atypical meningioma), the patient elected for surgical intervention. Histopathological examination confirmed a high-grade glioma (WHO grade 3) with oligodendroglioma-like morphology (Fig. 2B). Critical IHC findings included GFAP positivity, focal Olig-2 expression, IDH1-R132H negativity, retained ATRX nuclear staining, a Ki-67 proliferation index reaching 30% in hotspots, NeuN expression, focal MGMT immunoreactivity, and little EMA expression (Fig. 2C–J).

FIG. 2.

Neuroimaging and histopathological findings of the high-grade glioma at the third surgical intervention. A: T1-weighted contrast-enhanced axial (left), coronal (center), and sagittal (right) MR images showing a recurrent left frontal lesion (5.5 × 4.8 cm) with inhomogeneous contrast enhancement and restricted diffusion. B: H&E staining at medium power (original magnification ×10) revealing a hypercellular infiltrative glial tumor; the inset at high power (original magnification ×40) demonstrates typical oligodendroglioma-like features, including dense branching “chicken wire” capillaries and tumor cells with prominent perinuclear halos (fried egg appearance). C–J: IHC staining (original magnification ×20) demonstrating strong and diffuse GFAP positivity (C), focal expression of Olig-2 (D), NeuN expression (E), retained nuclear ATRX staining (F), negativity for IDH1-R132H–mutant protein (G), focal MGMT immunoreactivity (H), sparse/little EMA expression (I), and an elevated Ki-67 proliferation index reaching 30% in hotspots (J).

Molecular Profiling Confirms Metachronous Primary Tumors

To further elucidate the diagnosis and explore potential shared features between the 2018 meningioma and 2025 glioma, next-generation sequencing (NGS) was performed on both tumor samples (Table 1). The 2018 meningioma exhibited a missense mutation in NCOR2, splice-site mutations in the introns of CHD4 and ELP1, and lacked genetic alterations typical of grade 3 meningiomas (e.g., CDKN2A/B deletion or TERT promoter mutation). Chromosomal analysis revealed deletions of 1p, 19q, and 22q but no evidence of chromosome 7 amplification or chromosome 10 deletion (+7/−10). Histopathologically, the tumor met the 2021 WHO criteria⁸ for atypical meningioma (WHO grade 2), demonstrating increased mitotic activity, brain infiltration, and at least three high-grade features (e.g., high cellularity, nuclear atypia, and spontaneous necrosis). In contrast, the 2025 glioma harbored IDH2 p.R172H, TERT promoter mutation, NOTCH1 mutation, and CIC mutation, alongside 1p/19q co-deletion but not +7/−10. Despite the shared 1p/19q deletions—a finding that initially suggested a potential link—the mutually exclusive mutational profiles (e.g., IDH2 mutation in 2025 but not in 2018) and distinct IHC patterns supported the diagnosis of metachronous primary tumors: an atypical meningioma (2018) and an IDH-mutant (specifically IDH2 p.R172H) high-grade glioma with 1p/19q co-deletion (2025, WHO grade 3).

TABLE 1.

List of gene/chromosome variations from NGS

Gene/Chromosome	Nucleotide (amino acid) Change	VAF/Status
		Meningioma	Oligodendroglioma
CHD4	c.1686+1G>A	2.42%	—
NCOR2	c.6422C>T(p.T2141I)	2.01%	—
ELP1	c.3572+1G>A	2.00%	—
IDH2	c.515G>A(p.R172K)	—	43.03%
TERT	c.-124C>T	—	38.75%
CIC	c.2838G>A(p.W946*)	—	22.20%
CIC	c.3179+1G>A	—	0.99%
CIC	c.2923_2930del(p.V975Qfs*8)	—	0.80%
KRAS	c.35G>A(p.G12D)	—	50.70%
PIK3CA	c.2908G>A(p.E970K)	—	44.00%
PIK3CA	c.1357G>A(p.E453K)	—	4.56%
PIK3CA	c.3140A>G(p.H1047R)	—	2.75%
SETD2	c.5017A>T(p.K1673*)	—	4.11%
NOTCH1	c.1432T>G(p.C478G)	—	1.84%
FLT1	c.2507G>A(p.G836E)	—	1.51%
NOTCH1	c.1154C>T(p.S385F)	—	1.48%
PDGFRA	c.1886T>G(p.L629R)	—	1.08%
SETD2	c.4715+1G>A	—	0.91%
KDM5C	c.421C>T(p.L141F)	—	0.90%
CDKN2C	CNV	—	CN:1.02
1p	CNV	Deletion	Deletion
22q	CNV	Deletion	Normal
19q	CNV	Deletion	Deletion
Chr7	CNV	Normal	Normal
Chr10	CNV	Normal	Normal

CNV = copy number variation; VAF = variant allele frequency; — = not detected.

Literature Review

Based on our systematic literature search using the PubMed/MEDLINE database with a comprehensive search strategy combining glioma-related terms (“glioma”[MeSH], “glioblastoma”[Title/Abstract], “astrocytoma”[Title/Abstract], “oligodendroglioma”[Title/Abstract]) and meningioma-related terms (“meningioma”[MeSH], “meningioma”[Title/Abstract], “meningeal tumor”[Title/Abstract]) restricted to case reports and case series, we identified 8 relevant cases (Table 2) of meningioma and glioma coexistence or sequential occurrence in patients without prior cranial radiotherapy. The included patients ranged in age from 30 to 72 years (mean 53.0 years) with equal sex distribution (4 males, 4 females). All cases demonstrated either simultaneous coexistence or metachronous development of meningioma and glioma within adjacent anatomical regions. Meningioma subtypes encompassed both typical and atypical variants, while gliomas represented a broad histological spectrum ranging from low-grade astrocytomas to high-grade lesions (WHO grade 3, including glioblastoma). Molecular and IHC profiling revealed substantial heterogeneity among cases. Available data, although incomplete, demonstrated variable molecular features: IDH status ranged from mutant to wildtype or was unreported, Ki-67/MIB-1 indices showed considerable variation (from < 1% to elevated proliferative rates), and GFAP expression patterns were inconsistent, supporting distinct cellular lineages for the two tumor types. Primary management involved surgical intervention, with adjuvant chemotherapy or radiotherapy administered in select cases based on tumor grade and recurrence patterns. Follow-up data were variably reported across studies, limiting comprehensive outcome analysis.

TABLE 2.

Summary of published cases

Authors & Year	Case No.	Age (yrs)	Sex	Histology	WHO Grade	Location	Treatment Before Recurrence	IDH Mutation	Ki-67/MIB-1 (%)	GFAP+?
Matyja et al., 199515	1	46	M	Anaplastic astrocytoma†	UK	Rt frontal lobe	RT	Yes	UK	Yes
				Meningioma*	UK	Rt frontal lobe		UK	UK	Yes
Zhang et al., 20183	2	66	F	Glioblastoma†	IV	Rt temporal-parietal lobe	No	UK	UK	Yes
				Meningioma*	I	Rt temporal-parietal lobe		UK	UK	UK
Romero-Luna et al., 202416	3	54	M	Glioblastoma†	4	Rt occipital region	No	Yes	10	UK
				Atypical meningioma*	2	Rt occipital region		UK	UK	UK
Ohba et al., 201113	4	72	M	Glioblastoma†	UK	Rt frontal protuberance	No	Yes	18.6	Yes
				Frontal eminence meningioma*	UK	Rt frontal protuberance		UK	0.7	UK
Pereira et al., 201014	5	70	F	Glioblastoma†	IV	Rt frontal lobe	No	UK	UK	UK
				Parasellar meningioma*	II	Rt frontal lobe		UK	UK	UK
Li & Cheng, 200118	6	36	M	Malignant astrocytoma†	UK	Lt frontal region	No	UK	UK	Yes
				Endothelial cell type meningioma*	UK	Lt frontal region		UK	UK	UK
Li & Cheng, 200118	7	50	F	Anaplastic astrocytoma†	UK	Lt temporal lobe base	No	UK	UK	Yes
				Endothelial cell type meningioma*	UK	Lt temporal lobe base		UK	UK	UK
Wang et al., 201317	8	30	F	Temporal-parietal glioma†	IV	Rt temporal-parietal lobe	No	UK	UK	UK
				Malignant meningioma*	III	Rt temporal-parietal lobe		UK	UK	UK

RT = radiotherapy; UK = unknown.

* Pathological type at first diagnosis.

† Pathological type at recurrence/second diagnosis.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

There have been numerous reports in the world literature of cases in which intracranial meningiomas and gliomas occur successively. However, the occurrence of three different histological types of tumors in adjacent locations—specifically a low-grade astrocytoma, an atypical meningioma, and a high-grade glioma—in a patient without a history of radiotherapy or a family history of tumors is extremely rare. This rarity emphasizes the importance of detailed documentation, as it provides a unique perspective for understanding the complex biological mechanisms underlying the sequential occurrence and progression of CNS tumors independent of radiation triggers.

Classification and Collision Tumor Definitions

Collision tumors are generally categorized into synchronous and metachronous types.⁹ Synchronous collision tumors, as summarized in Table 2, involve the simultaneous diagnosis of histologically distinct neoplasms. These cases often suggest a shared pathogenic mechanism or exposure to common oncogenic factors within a specific anatomical region. In contrast, metachronous collision tumors, such as the one described in our report, develop sequentially. These may reflect a unique genetic predisposition, alterations in the local microenvironment, or tumor induction related to prior clinical interventions.^9–11 While postradiotherapy metachronous tumors are well documented (often linked to radiation-induced deletion or mutation of the NF2 gene locus at 22q12),^5,10,12 cases occurring without radiation therapy, similar to ours, are rare (Table 2).^3,13–18

Potential Pathogenic Mechanisms

The mechanism of primary intracranial metachronous collision tumors remains unclear, but multiple potential hypotheses may explain our findings. First, the tumors may share a “common microenvironment” where local paracrine signaling, extracellular matrix composition, and microvascular structures promote the development of different tumor types over time.^9,10 Second, the inflammatory response and tissue repair process following the initial surgical intervention in 2000 may have stimulated abnormal glial cell proliferation and subsequent malignant transformation. Third, it is possible that tumor stem cells with multipotential differentiation capacity underwent abnormal lineage commitment, leading to histologically distinct tumors in the same region.¹⁰ Whether these tumors can transform into each other remains controversial; while some view them as independent events, others suggest potential lineage plasticity.¹⁹

Molecular Evolution and Evidence of Independence

The molecular analysis of the patient’s tumors revealed both shared and unique features. Both the 2018 meningioma and the 2025 glioma exhibited a 1p/19q co-deletion. However, 22q deletion and specific alterations in CHD4, NCOR2, and ELP1 were only observed in the meningioma. Conversely, the 2025 high-grade glioma harbored IDH2 (p.R172H) and TERT promoter mutations, which are diagnostic hallmarks of glioma. The presence of distinct driver mutations suggests that despite certain overlapping alterations, these tumors are independent entities. Under the condition that medical records are accurate, shared markers might involve common oncogenic factors such as P53, VEGF, EGFR, and PDGFR,¹⁰ suggesting a localized “field cancerization” effect rather than a direct clonal transition from meningioma to glioma.

Limitations and Clinical Implications

This case has notable limitations. Most significantly, the medical records and imaging data from the initial 2000 astrocytoma surgery have been lost, making it difficult to confirm the initial pathological subtype or track the complete molecular evolution from the very beginning. Additionally, the lack of complete information on the 2000 chemotherapy regimen may affect our understanding of the tumor’s natural history. Despite these gaps, this case underscores the necessity of integrated molecular analysis and long-term longitudinal monitoring. Studying such rare occurrences is crucial for clarifying tumor-to-tumor interactions and malignant progression. Furthermore, while our NGS analysis of tumor tissue provided robust evidence for the independent clonal origins of the meningioma and the glioma, the absence of germline mutation analysis (e.g., blood-based sequencing) remains a limitation. Given the rarity of triple primary tumors in a single patient, a genetic predisposition, such as a subtle variant of Li-Fraumeni syndrome or other hereditary cancer syndromes, cannot be entirely excluded, despite the lack of a positive family history. Future research on such complex cases should prioritize paired tumor-germline sequencing to fully elucidate whether these occurrences stem from a shared genetic susceptibility or purely localized microenvironmental factors.

Lessons

This case provides several important insights for clinical practice and research. First, it highlights that sequential and metachronous primary intracranial tumors can occur in the same anatomical region even in the absence of a history of cranial radiotherapy. Clinicians should be highly vigilant when evaluating recurrent or new lesions in patients with a history of brain tumors, as imaging alone may not reliably distinguish tumor types. Second, the case underscores the importance of comprehensive histopathological and molecular assessment (including NGS) to accurately differentiate between different tumor types and identify potential common or differential molecular features. Third, it indicates that collision tumors may involve complex interactions of local microenvironmental factors, stem cell plasticity, and possible intertumor signaling, further emphasizing the importance of going beyond traditional histological understanding of tumor biology. Finally, it stresses the necessity of long-term follow-up and detailed documentation, as sequential tumors may occur years or even decades after the initial diagnosis, and early identification can provide a basis for surgical planning, targeted therapy, and prognosis counseling. Overall, it contributes to the growing body of knowledge on primary intracranial collision tumors and provides insights into their diagnosis, pathogenesis, and management.

Acknowledgments

Funding is acknowledged from the National Natural Science Foundation of China (NSF) (82571477 to Z.W.).

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Zhang, F Wang, Chang, Qiu, You, Z Wang. Acquisition of data: F Wang, Chang, Yan, Qiu, You, Z Wang. Analysis and interpretation of data: Zhang, F Wang. Drafting the article: F Wang, Chang. Critically revising the article: Zhang, F Wang, Qiu, M Wang, Z Wang. Reviewed submitted version of manuscript: Zhang, F Wang, M Wang, You, Z Wang. Approved the final version of the manuscript on behalf of all authors: Zhang. Statistical analysis: Chang, Qiu, M Wang. Administrative/technical/material support: Zhang. Study supervision: Zhang, You.

Correspondence

Juyi Zhang: The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China. zhangjuyi123456@163.com.